Billy Vunipola will miss England's autumn Test campaign after breaking his arm for the third time this year.
The Saracens number eight suffered the injury to his left arm in Saturday's 13-3 Champions Cup win at Glasgow and will undergo surgery on Tuesday.
Prop Mako Vunipola's calf strain and lock Nick Isiekwe's ankle sprain will also hand England boss Eddie Jones further headaches, with both now huge doubts to take part in England's autumn schedule.
Billy Vunipola's latest setback only piles on the misery for England's talisman back-row forward, who missed the 2017 British and Irish Lions tour after shoulder surgery before serious knee trouble and two consecutive right-arm fractures denied him yet more Test match honours.
"Nick Isiekwe, Billy Vunipola and Mako Vunipola are set for a spell on the sidelines," Saracens confirmed in a statement.
"The trio were all forced off in Saracens' Heineken Champions Cup win over Glasgow Warriors on Sunday.
"Isiekwe suffered an ankle sprain and is waiting to be assessed by a consultant with regards to the full extent of the injury.
"Billy has fractured his left arm and will have surgery on Tuesday. He is expected to be out of action for around 12 weeks.
"Mako picked up a calf strain and his progress will be monitored."
Only last month, Billy Vunipola struck a disarmingly honest chord when admitting he had previously tried to "be a hero" and play through the pain of injury.
So, just when Saracens and England were hoping he would hit peak fitness and form for an overdue and deserved extended run of matches, once again he has been forced back into the operating theatre.
The 25-year-old's absence will put a significant dent in England and boss Jones' resources for the November clashes with South Africa, New Zealand, Japan and Australia.
Exeter's Sam Simmonds is already out of the autumn equation after tearing knee ligaments, leaving England now lacking a specialist number eight.
Gloucester's Ben Morgan, deemed surplus to Test requirements since the 2015 World Cup, is fit and in form, so could now come into head coach Jones' reckoning.
Mako Vunipola's potential November Test absence would prove another blow to an England pack already missing fellow experienced loosehead prop Joe Marler, who has opted to retire from international rugby.
Fast-improving Lock Isiekwe has already won three caps and would be pushing hard for Test time, barring injury concerns.